Antifibrinolytic compounds

ABSTRACT

THE COMPOUND 4 - (A - AMINO LOWER ALKYL) BICYCLO(2.2.2)-OCTANE-1-CARBOXYLIC ACID AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF ARE USEFUL AS ANTIFIBRINOLYTIC COMPOUNDS.

United States Patent Oflice 3,641,128 Patented Feb. 8, 1972 ABSTRACT OFTHE DISCLOSURE The compound 4 (a amino lower alkyl)bicyclo-[2.2.2]-octane-1-carboxylic acid and the pharmaceutically acceptablesalts thereof are useful as antifibrinolytic compounds.

This invention relates to a new antifibrinolytic compound and to amethod of counteracting certain hemorrhagic conditions and otherdisorders resulting from a pathological fibrinolytic state in patients.More specifically, this invention relates to a new compound of thestructure i u uca-@ coon wherein R is lower alkyl and thepharmaceutically acceptable salts thereof. More specifically, it relatesto the prevention or treatment of a pathological fibrinolytic state inpatients by the oral administration of from 1 to 20 and preferably 2 to8 mg./kg. of body weight per day of the above compounds for varyingperiods of treatment.

The dissolution of fibrin deposits in mammals is due to their lysis bythe enzyme plasmin (fibrinolysin) which is formed in the blood fromplasminogen, also present in the blood. This conversion from plasminogento plasmin is promoted by activators in the blood and it would appearthat excessive fibrinolytic activity results from an overabundance ofsuch activators. When too much plasmin is present, the clotting systemof the blood becomes unbalanced, viable clots cannot be maintained, andhemor rhage may result. This situation is known as a fibinolytic state.Other enzyme systems (i.e., the kallikreins, complement) may also beactivated in an undesirable manner when such a state exists.

An interest has recently developed in antifibrinolytic agents, i.e.drugs which will inhibit the activation of plasminogen to form plasmin.These antifibrinolytic agents are believed to interfere with thefunction of the activators of converting plasminogen to plasmin. Theclinical uses of such drugs include their administration to personsundergoing various kinds of surgery (such as heart-lung and prostatesurgery), obstetrical hemorrhage problems, menorrhagia, and many otheruses which have been suggested in the literature (e.g. see Nilssen, ActaMedica Scand. Suppl. 448, volume 180, 1966).

A standard antifibrinolytic agent, against which newer ones aregenerally tested and compared is epsilon aminocaproic acid, known asEACA. One deficiency of this agent has been the very high dosagesneeded; in some cases 3-6 grams or more every 4 to 6 hours. Also, sideeffects such as dizziness, nausea and diarrhea have been observed. Morerecently, two more potent agents have been described, namelytrans-4-aminomethylcyclohexane carboxylic acid (AMCHA) and4-aminomethylbenzoic acid (PAMBA). Each is reported to be more activethan EACA by both in vitro and in vivo tests (e.g. see Anderssen et al.Scand. J. Haemat. (1965) 2, 230 and Melander et al. Acta Pharmacol. etToxicol 22, 340 (1965 both of which discuss AMCI-IA).

I have found a new class of aminomethyl bicyclic carboxylic acids whichshow an activity of about 50 times that of EACA in tests essentially thesame as those known to correlate with clinical results. I have thus alsofound an improved antifibrinolytic method of therapeutic treatmentrequiring much smaller doses of the drug.

The new compound of my invention has the general wherein R is loweralkyl. The compound can be used as the racernate or either the d or 1isomer. The pharmaceutically acceptable salts of the compound also showantifibrinolytic activity.

The present invention also provides a process of preparing a compound ofthe structure which comprises the catalytic hydrogenation of a compoundof the structure wherein R is lower alkyl. The hydrogenation is carriedout under conventional conditions'generally in the presence of acatalyst such as platinum. In a preferred embodiment of the presentinvention, the lower alkyl group R of 1 to 5 carbon atoms. is eithermethyl or ethyl.

The compound is used in the method of this invention by either oral orintravenous administration, although the oral route is preferred. Theesters and amides of this class compound are not themselves very activein vitro but the action of enzymes in vivo cause the slow liberation ofthe highly active amino acids, thus providing a prolonged availabilityof the drug in the body. This is important because of the tendency ofthese drugs to be swiftly eliminated in the urine. Such amides andesters are to be considered as being within the scope of the presentinvention since it is actually the present compound which produces theresult within the body.

The compound of this invention can be used in a composition comprisingany pharmaceutically acceptable carrier, in the form of pills, tabletsor capsules. The pharmaceutically acceptable salts (both of the aminogroupsuch as the hydrochloride, hydrobromide, sulfate, citrate,tartrate, etc.and of the carboxy group-such as the alkali metal,alkaline earth metal, etc., salts) are readily usable, especially ininjectable compositions.

The invention can be illustrated by the cfollowing examples.

EXAMPLE 1 Racemic 4-(a-aminoethyl)-bicyclo-[2.2.21-octane-lcarboxylicacid (A) 4-carbomethoxybicyclo [2.2.2] oct-2-ene-1-carboxylic acidchloride.--A solution of 5.0 g. (0.024 mole) methylhydrogenbicyclo-[2.2.2]-oct 2 ene-1,4-dicarboxylate [F. W. Baker and L.M. Stock, J. Org. Chem. 32 3344 (1967)] in 20 ml. of thionyl chloride isheated to reflux for 3 hours. After removal of the excess thionylchloride by distillation in vacuo at steam bath temperatures and thenreevaporation with 3-20 ml. portions of hexane, the resulting liquid isdistilled in vacuo, giving 3 5.3 g. (97%) of a colorless liquid, B.P.97-98 C./7.0 mmpHg.

(B) 4-acetylbicycl0 [2.2.2] oct-2-ene-l-carboxylic acid.A mixture of0.42 g. (0.017 mole) magnesium turnings, 2 ml. dry benzene and 0.1 ml.absolute ethanol is heated to reflux until the dissolution of magnesiumbegins. To this is added, over 30 minutes, a mixture of 2.72 g. (0.017mole) diethyl malonate, 0.7 ml. absolute ethanol and 3 ml. benzene.After 3 hours of reflux, all of the magnesium has dissolved. The ethanolis then removed by azeotropic distillation with fresh portions ofbenzene, the volume brought to about ml. with benzene, and a solution of3.43 g. (0.015 mole) 4-ca.rbomethoxybicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid chloride in 5 ml. benzene is addedat reflux over a minute period. After an additional 3 /2 hours atreflux, the viscous mixture is poured into 100 ml. ice water and ml. 6 Nhydrochloric acid. The combined benzene extracts, after washing withwater and drying over MgSO gives 4.5 g. of a colorless liquid, aninfrared spectrum of which exhibited no acid chloride absorption. Thetriester is hydrolyzed directly without purification by refluxing for 16hours with a mixture of 25 ml. glacial acetic acid and 25 ml.concentrated hydrochloric acid. Evaporation leaves 1.83 g. (63% crude)of a white solid, which is chromatographed on silica gel (CHCl eluant)to remove a minor slower moving impurity. The chromatographed materialis recrystallized from benzene-hexane, giving a white crystalline solid,M.P. 1655-168 C.

(C) 4-(a-oximinoethyl)-bicyclo-[2.2.2]-oct 2 ene-lcarboxylic acid.Amixture of 0.52 g. (7.5 mmoles) hydroxylamine hydrochloride, 3 ml.absolute ethanol and 3 ml. pyridine is refluxed on a steam bath for 5minutes. To this is added 0.49 g. (2.5 mmoles) 4-acetylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid. After 3 hours at reflux, most of thesolvent is removed in vacuo, then the residue is stirred with 30 ml.cold 3 N hydrochloric acid. The resulting crystalline solid iscollected, washed with water and air-dried. Weight: 0.44 g. M.P. 242-245C. The material is recrystallized from ethanol or ethyl acetate, M.P.245247 C.

(D) dl-4-(a-aminoethyl)-bicyclo [2.2.2] octane-1- carboxylic acidhydrochloride.To a solution of 270 mg. (1.29 mmoles) 4-(a-oximinoethyl)bicyclo-[2.2.2]-oct 2-ene-l-carboxylic acid in 50 ml. 90% ethanol isadded 0.5 ml. 6.0 N hydrochloric acid and 50 mg. platinum oxide. Themixture is shaken in a Parr hydrogenation apparatus at 30 lbS./in. and25 C. for 3 hours. Filtration and evaporation leaves a white solid,which is recrystal lized from ethanol-ether. Yield: 240 mg. (80%). The

material, which is not noticeably hydroscopic, is purified byrecrystallization from ethanol-ether and dried for anallysis at C. invacuo, M.P. 313.5-315 C. dec.

EXAMPLE 2 The compound is tested in vitro by measuring the effect of theinhibitor at various concentrations on the lysis times of a fibrin clotwith a constant concentration of streptokinase in plasminogen-richplasma. The concentration of the inhibitor which increases the geometricmean lysis time by 50% is estimated. Epsilon amino caproic acid (EACA)is used as a standard and the relative potencies are obtained, with thefollowing results:

Compound: Relative in vitro activity (weight basis) (A) Referencecompound: EACA 1.0

(B) New compound: 4-(a-aminoethyl)bicyclo- [2.2.2] octane-l-carboxylicacid 50 Many other equivalent modifications of the invention would beapparent to those skilled in the art from a reading of the foregoingwithout a departure from the inventive concept.

.I claim:

1. A compound selected from the group consisting of n ncn @coouReferences Cited UNITED STATES PATENTS 6/1970 Loefpler 2605l4 OTHERREFERENCES House, Modern Synthetic Reactions, p. 15, 1965.

LEWIS GOTTS, Primary Examiner R. GERSTL, Assistant Examiner U.S. Cl.X.R.

260468 B, 501.11, 557 B; 424-3l9

